The significant progress made over the past several decades in the medical treatment of HIV/AIDS has made addressing tobacco use a critical health issue in this population. Unfortunately, 50-74% of individuals with HIV/AIDS are regular smokers which reduce viral and immunologic response to anti-retroviral medications (HAART), increases cardiovascular risk factors exacerbated by HAART, and worsens HIV symptoms and quality of life (QOL). To date, this sub-group of smokers has been critically under-studied by tobacco control researchers. Individuals with HIV/AIDS have been excluded from large clinical trials of nicotine dependence medications because of their diagnosis or because of co-occurring medical and psychiatric conditions which can affect response to treatments for nicotine dependence and only three smoking cessation clinical trials have been conducted with those with HIV/AIDS. As such, the current literature on smoking cessation treatments may not generalize to the population of smokers with HIV/AIDS, including both the efficacy and the safety of medications for use to treat nicotine dependence, and there is a paucity of empirical data on which to base recommendations for the treatment of nicotine dependence among those with HIV/AIDS. This has led the US Public Health Service to call for the systematic evaluation of nicotine dependence treatments for this sub-group of smokers as a critical priority. The present study will represent the first randomized placebo-controlled clinical trial of varenicline for nicotine dependence among smokers with HIV/AIDS. Varenicline is the most efficacious medication for nicotine dependence in the general population of smokers and may be particularly efficacious for smokers with HIV/AIDS since these smokers experience high levels of psychological distress and cognitive impairment which can be mitigated by varenicline. This trial is powered to adequately evaluate efficacy and safety, and may help fill a critical gap in th nicotine dependence literature as well as the literature relied upon to guide the clinical care of patients with HIV/AIDS. With a sample of 310 smokers diagnosed with HIV/AIDS we will address the following aims: 1) Compare 12-weeks of varenicline treatment and behavioral counseling to 12-weeks of placebo treatment and behavioral counseling for treating nicotine dependence among individuals with HIV/AIDS~ 2) Assess effects of varenicline therapy on QOL and varenicline associated side effects~ and 3) Assess changes in affect and cognitive performance as mediators of varenicline therapy's effect on quit rates. We will also explore participant-related variables as moderators of varenicline therapy's effect on quit rates. Overall we expect that this study will provide the data necessary to guide the use of varenicline for the treatment of nicotine dependence among those with HIV/AIDS, thereby potentially offering an efficacious strategy to reduce tobacco-related morbidity and mortality in this under-served community of smokers.